1 Zobair Younossi, MD, MPH, FACG Falls Church, VA, United States This activity is supported by an...

1

Best of HCV from EASL 2014

Zobair Younossi, MD, MPH, FACGFalls Church, VA, United States

This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb, Gilead Sciences and Janssen Therapeutics

2


• Candidacy for Treatment of HCV Patients: The Clinical Experience from Kaiser Permanente

• The New Treatment Regimens for HCV

• Assessment of Patient-related Outcomes During HCV treatment

3

Abstract #O67

Comorbid Conditions Associated With Decision-Making Regarding Treating or Not Treating Chronic Hepatitis C in a

Large U.S. Health Maintenance Organization

L.M. Nyberg1, K.M. Chiang2, Z. Li2, A.H. Nyberg1, Z.M. Younossi3, T.C. Cheetham2

1Hepatology Research, Kaiser Permanente, San Diego, 2Pharmacy Analytical Services, Kaiser Permanente, Downey, CA, 3Department of Medicine, Inova Fairfax Hospital, Center for Liver Diseases, Falls Church, VA,

United States

4Nyberg, L. et al. EASL 2014, Abstract #O67

Methods

• Study Design

– A retrospective study using the database of Kaiser Permanente, Southern California, a large Health Maintenance Organization including 3.5 – 4 million members

• Inclusion Criteria

– ≥ 18 years old with a diagnosis code or a positive lab test result for HCV RNA from January 1, 2002 through December 31, 2012

– ≥ 6 months continuous membership plus drug benefit prior toHCV treatment

– Index date was defined as the date of the first treatment course or first chronic HCV diagnosis


Methods

• Identification of comorbid illnesses representing relative or absolute contraindications to HCV treatment with interferon-based therapy were determined by diagnosis codes and/or lab tests for

– Comorbid illness identified in the study: cancer, anemia, autoimmune disorder, renal dysfunction, thrombocytopenia, diabetes, HIV, CVD, psychosis/bipolar disorder, depression, severe lung disease, substance abuse, Hepatitis B, MELD ≥ 12

• Multivariate logistic regression was used to determine predictors of treatment vs non-treatment


Results

Entire Population(Patients with a diagnosis code

or positive lab test for HCV)

Study Population(After applying

inclusion/exclusion criteria)

N=51,984 patients

7,945 patients (15%) ofthis population received treatment

N= 32,283 patients

5,533 patients (17%) inthe study population received treatment


Results

Entire Population(Patients with a diagnosis code

or positive lab test for HCV)

Study Population(After applying

inclusion/exclusion criteria)

N=51,984 patients

7,945 patients (15%) of this population received treatment

N= 32,283 patients

5,533 patients (17%) inthe study population received treatment

8

Study PopulationN=32,283

Not TreatedN=13,702 (85%)

TreatedN=2,484 (15%)

With at least 1 Significant Comorbid Illness N=16,186 (50%)

Nyberg, L. et al. EASL 2014, Abstract #O67

Results

• In the patients with at least 1 significant comorbid illness

9

• 50% (16,186/32,283) of the study population had a significant comorbid illness

– 15% (2,484/16,186) were treated

– 85% (13,702/16,186) were not treated

Study PopulationN=32,283

Not TreatedN=13,702 (85%)

TreatedN=2,484 (15%)

With at least 1 Significant Comorbid Illness N=16,186 (50%)

Nyberg, L. et al. EASL 2014, Abstract #O67

Results

• In the patients with at least 1 significant comorbid illness


Results

Factors Associated with Receiving Treatment

• In multivariate logistic regression analysis, factors associated with receiving treatment included younger age (age<65), male gender, presence of cirrhosis, HIV co-infection, and a history of liver transplantation (P = 0.0012 to <0.0001)


Results

Factors Associated with NOT Receiving Treatment

• In multivariate logistic regression analysis, factors associated with not receiving treatment for HCV included presence of anemia, autoimmune disorders, renal dysfunction, CVD, psychosis/bipolar, substance abuse, severe lung disease and MELD>12 (P = 0.0195 to <0.0001)


Summary

• In this large database representing a real world population, only 15-17% of those identified with HCV were treated with interferon-based regimens

• 42% of the total study population were likely interferon ineligible or intolerant

• 50% had no apparent contraindications to interferon-based therapy

• 50% had comorbid conditions representing relative or absolute contraindications to interferon-based therapy

• New, interferon-free regimens may offer new treatment options for this group

13


• Candidacy for Treatment of HCV Patients: The Clinical Experience from Kaiser Permanente

• The New Treatment Regimens for HCV

• Assessment of Patient-related Outcomes During HCV treatment

14

Abstract #O165

Simeprevir Plus Sofosbuvir With/Without Ribavirin inHCV Genotype-1 Prior Null-responder /

Treatment-naïve Patients (COSMOS Study): Primary Endpoint (SVR12) Results in Patients With METAVIR F3-4 (Cohort 2)

E. Lawitz1, R. Ghalib2, M. Rodriguez-Torres3, Z.M. Younossi4, A. Corregidor5, M.S. Sulkowski6,E. DeJesus7, B. Pearlman8, M. Rabinovitz9, N. Gitlin10, J.K. Lim11, P.J. Pockros12, B. Fevery13,T. Lambrecht14, S. Ouwerkerk-Mahadevan13, K. Callewaert13, W.T. Symonds15, G. Picchio16,

K. Lindsay16, M. Beumont-Mauviel13, I.M. Jacobson17

1Texas Liver Institute, San Antonio, 2Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, 3Fundaci_n de Investigaci_n, San Juan, PR, 4Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, 5Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, 6Johns Hopkins University School of Medicine, Baltimore, MD, 7Orlando Immunology Center, Orlando, FL, 8Atlanta Medical Center,

Atlanta, GA, 9University of Pittsburgh Medical Center, Pittsburgh, PA, 10Atlanta Gastroenterology Association, Atlanta, GA, 11Yale School of Medicine, New Haven, CT, 12Scripps Clinic, La Jolla, CA, United

States, 13Janssen Research & Development, Beerse, 14Novellas Healthcare, Zellik, Belgium, 15Gilead Sciences Inc, Foster City, CA, 16Janssen Research & Development LLC, Titusville, NJ, 17Weill Cornell

Medical College, New York, NY, United States

15

• Cohort 1: METAVIR F0-F2, prior null responders• Cohort 2: METAVIR F3-F4, prior null responders or treatment-naïve

– Stratified by treatment history, HCV GT 1a/1b

• Primary endpoint: SVR12 • Secondary endpoints: RVR, on-treatment failure, relapse rate, safety and tolerability

BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentLawitz, E. et al. EASL 2014, Abstract #O165

COSMOS Study Design: Randomised, Multicentre, Open-label Trial

0 4 12 24 36 48Week

SMV + SOF + RBV Post-treatment follow-up

SMV + SOF Post-treatment follow-up

Post-treatment follow-up

Post-treatment follow-upSMV + SOF

Arm 1

Arm 2Randomised2:1:2:1

Arm 3

Arm 4

SMV + SOF + RBV

SMV 150 mg QD + SOF 400 mg QD±RBV 1000/1200 mg/day (BID)

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Non-VF, patients who did not achieve SVR12 for reasons other than virologic failureITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment endBID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentLawitz, E. et al. EASL 2014, Abstract #O165

COSMOS Cohort 2: SVR12 – Primary Endpoint (ITT population)

0

20

40

60

80

1007% 7% 7%

SMV/SOF±RBV

Pro

po

rtio

n o

f p

atie

nts

(%

)

SMV/SOF + RBV SMV/SOF + RBVSMV/SOF SMV/SOF

24 weeks 12 weeks Overall

SVR12 Non-VF Relapse

93% 100% 93%93% 94%

2/30 1/142/27 3/872/87

28/30 16/16 13/1425/27 82/87

3%2%

17

GT, genotype; ITT, Intent-to-treat; QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatmentLawitz, E. et al. EASL 2014, Abstract #O165

COSMOS Cohort 2: Conclusions

• SMV/SOF QD led to SVR12 rates of 93-100% (ITT)

in HCV GT 1 infected treatment-naïve and prior null-responder patients with METAVIR F3-4

• SVR12 rates were high, regardless of baseline characteristics:– HCV GT 1 subtype, Q80K polymorphism, METAVIR

score, IL28B GT, prior treatment history

• SMV/SOF QD +/- RBV was safe and well tolerated

• Two Phase 3 trials investigating SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2)

18

J.J. Feld1, K.V. Kowdley2, E. Coakley3, S. Sigal4, D. Nelson5, D. Crawford6,7, O. Weiland8, H. Aguilar9, J. Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3

1Toronto Western Hospital Liver Centre, Toronto, ON, Canada, 2Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, 3AbbVie Inc., North Chicago, IL, 4NYU Langone Medical Center, New York, NY, 5University of Florida College of Medicine, Gainesville, FL, United States, 6Gallipoli Medical Research

Foundation, 7The University of Queensland, Brisbane, QLD, Australia, 8Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden, 9Louisiana Research Center, LLC, Shreveport, LA,

United States

Abstract #O60

SAPPHIRE I: Phase 3 Placebo-Controlled Study Of Interferon-Free, 12-Week Regimen Of ABT-450/r/ABT-267, ABT-333, And Ribavirin In 631 Treatment-Naïve

Adults With Hepatitis C Virus Genotype 1

19

• 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir,250 mg BID

• RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively)

Week 0 Week 12 Week 24 Week 60 Week 72

3D + RBV(n=473)

Placebo(n=158) 3D + RBV

Double-BlindTreatment Period

Open-LabelTreatment Period

Primary Analysis: SVR12

48-WeekFollow-Up

48-WeekFollow-Up

Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Placebo-Controlled Design (N=631)

20

3D + RBV(N=473)

Placebo(N=158)

Male, n (%) 271 (57.3) 73 (46.2)Race, n (%) White 428 (90.5) 144 (91.1) Black 26 (5.5) 8 (5.1)Hispanic/Latino ethnicity, n (%) 27 (5.7) 5 (3.2)Median age, years (range) 52.0 (18.0-70.0) 52.0 (21.0-70.0)Median BMI, kg/m2 (range) 25.2 (18.0-38.4) 25.5 (18.5-39.4)Fibrosis stage, n (%)

F0-F1 363 (76.7) 116 (73.4)F2 70 (14.8) 27 (17.1)F3 40 (8.5) 15 (9.5)

IL28B non-CC genotype, n (%) 329 (69.6) 108 (68.4)HCV subtype, n (%) 1a 322 (68.1) 105 (66.5) 1b 151 (31.9) 53 (33.5)

Median HCV RNA, log10 IU/mL (range) 6.51 (3.58-7.60) 6.64 (3.71-7.51)

HCV genotype and subtype were assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0.Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Baseline Patient Characteristics

21Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I Results: ITT SVR12 Rates (Superiority to Calculated Placebo Rate)

SV

R1

2, %

Pa

tien

ts

All Patients

96.2% 95.3% 98.0%

455/473 307/322 148/151

GT1a GT1b

22Feld, J. et al. EASL 2014, Abstract #O60

SAPPHIRE-I: Conclusions

• The ITT SVR12 rate was 96.2% (455/473) for treatment-naïve GT1-infected patients receiving 12 weeks of co-formulated ABT-450/r/ombitasvir + dasabuvir + RBV

• SVR12 rates (ITT) were high regardless of HCV subtype

• The rate of virologic failure was low:– 0.2% breakthrough rate

– 1.5% relapse rate

• The regimen was generally well-tolerated, with a low rate of study drug discontinuation due to AE(s) (0.6%)

23

M. Manns1, S. Pol2, I. Jacobson3, P. Marcellin4, S. Gordon5, C.-Y. Peng6, T.-T. Chang7, G. Everson8, J. Heo9, G. Gerken10, B. Yoffe11, W.J. Towner12, M. Bourliere13, S. Metivier14, C.-J. Chu15, W. Sievert16, J.-P. Bronowicki17, D. Thabut18, Y.-J. Lee19, J.-H. Kao20, F. McPhee21, J. Kopit21, P. Mendez22, M. Linaberry22,

E. Hughes22, S. Noviello22, HALLMARK DUAL Study Team1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, 2Hopital Cochin, Paris, France, 3Weill Cornell Medical College, New York, NY, United States,

4Hopital Beaujon, Clichy, France, 5Henry Ford Health Systems, Detroit, MI, United States, 6School of Medicine, China Medical University, Taichung, 7National Chen Kung University Hospital, Tainan, Taiwan, 8University Of Colorado Denver, Aurora, CO, United States, 9Pusan National University Hospital, Busan,

Korea, Republic of, 10University of Duisburg-Essen, Essen, Germany, 11VAMC, Baylor College of Medicine, Houston, TX, 12Kaiser Permanente, Los Angeles, CA, United States, 13H_pital Saint Joseph, Marseille,

14CHU Purpan, Toulouse, France, 15Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, 16Monash Health and Monash University, Melbourne, VIC, Australia, 17INSERM Unit_ 954,

Centre Hospitalier Universitaire de Nancy and Universit_ de Lorraine, Vandoeuvre-l_s-Nancy, 18H_pital Piti_-Salp_tri_re, Paris, France, 19Inje University Busan Paik Hospital, Busan, Korea, Republic of, 20National Taiwan University Hospital, Taipei, Taiwan, 21Bristol-Myers Squibb Research and Development, Wallingford,

CT, 22Bristol-Myers Squibb Research and Development, Princeton, NJ, United States

Abstract #O166

All-Oral Dual Therapy With Daclatasvir And Asunaprevir In Patients With HCV Genotype 1b Infection: Phase 3

Study Results

24

• Primary endpoint: proportion of DCV + ASV-treated patients with SVR12

• Patients infected with HCV genotype 1b– Treatment-naive– Nonresponders: prior null or partial response to pegIFN/RBV– Interferon-ineligible/intolerant (treatment-naive or -experienced) due to

• Depression• Anemia/neutropenia• Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia

24

Ran

dom

izat

ion

2:1

STOP

DCV + ASV 24 weeks(N = 205)

DCV + ASV 24 weeks(N = 235)

Week 24 Week 48Day 1 Week 12

Nonresponder

Ineligible/intolerant

Treatment-naive

DCV 60 mg QD + ASV 100 mg BID 24 weeks(N = 203)a

DCV-PBO + ASV-PBO 12 weeks (N = 102)

Enter another study:DCV + ASV 24 weeks

Follow up 24 weeks

Follow up 24 weeks

Follow up 24 weeks

SVR12

a Excludes 2 patients inadvertently assigned, instead of randomized, to DCV + ASV; patients were excluded from efficacy analyses but both achieved SVR12

Manns, M. et al. EASL 2014, Abstract #O166

Global Phase 3 Study: HALLMARK-DUAL (AI447-028)

25

ParameterTreatment-naive

DCV + ASV(N = 205)

Treatment-naivePlacebo(N = 102)

Nonrespondera

(N = 205)

Ineligible/intolerantb

(N = 235)

Age, median years 55 54 58 60

Male, n (%) 101 (49) 54 (53) 111 (54) 98 (42)

Race, n (%)

White 135 (66) 59 (58) 148 (72) 169 (72)

Black 14 (7) 8 (8) 10 (5) 10 (4)

Asian 52 (25) 33 (32) 45 (22) 56 (24)

HCV RNA, n (%)

< 800,000 log10 IU/mL 53 (26) 26 (25) 27 (13) 48 (20)

≥ 800,000 log10 IU/mL 152 (74) 76 (75) 178 (87) 187 (80)

Cirrhosis, n (%) 33 (16) 16 (16) 63 (31) 111 (47)

IL28B genotype, n (%)

CC 76 (37) N/A 29 (14) 82 (35)

Non-CC 129 (63) N/A 173 (84) 143 (61)a Includes 119 (58%) null responders, 84 (41%) partial responders, and 2 (1%) relapsers.b Includes 71 (30%) patients with depression, 87 (37%) with anemia/neutropenia, and 77 (33%) with compensated advanced fibrosis/cirrhosis with thrombocytopenia (6 with advanced fibrosis [F3], 70 with cirrhosis [F4], and 1 not reported).

Manns, M. et al. EASL 2014, Abstract #O166

Patient Baseline Characteristics

26

0

20

40

60

80

100 9082 82

Virologic Response: SVR12

Treatment-naive

Nonresponders Ineligible/intolerant

SV

R12

(%

of

pat

ien

ts)a,

b

• SVR12 rates documented on or after posttreatment Week 12– Treatment-naive: 91%– Nonresponders: 82%– Ineligible/intolerant: 83%

a HCV RNA < lower limit of assay quantitation (25 IU/mL)b Patients with missing SVR12 data counted as treatment failuresManns, M. et al. EASL 2014, Abstract #O166

182/203 168/205 192/235

27Manns, M. et al. EASL 2014, Abstract #O166

Summary

• All-oral DCV + ASV therapy achieved SVR12 rates up to 91% in treatment-naive, 82% in nonresponder, and 83% in ineligible/intolerant patients with genotype 1b

– SVR12 rates were similar in non-cirrhotic (85%) and cirrhotic (84%) patients

– No differences by age, gender, race, IL28B genotype, or prior IFN/RBV treatment experience

• DCV + ASV was generally safe and well tolerated– Only 2% of patients discontinued treatment due to

adverse events

• DCV is being further evaluated in all-oral combinations in multiple patient populations of high unmet need

28

Abstract #O10

Safety and Efficacy of the All-oral Regimen of MK-5172/MK-8742 + Ribavirin in Treatment-naïve, Non-cirrhotic Patients With Hepatitis C Virus Genotype 1

Infection: The C-WORTHy Study

C. Hezode1, L. Serfaty2, J.M. Vierling3, M. Kugelmas4, B. Pearlman5, W. Sievert6, W. Ghesquiere7, E. Zuckerman8, F. Sund9, M. Shaughnessy10, P. Hwang10, J. Wahl10, M.N. Robertson10, B. Haber10

1Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, 2Gastroenterology and Hepatology, H_pital Saint Antoine, APHP and INSERM UMR_938, Universit_ Pierre

& Marie Curie, Paris, France, 3Hepatology, Baylor College of Medicine, Houston, TX, 4South Denver Gastroenterology, PC, Englewood, CO, 5Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, United

States, 6Gastrointestinal and Liver Unit, Monash University, Clayton, VIC, Australia, 7Vancouver Island Health Authority, Victoria, BC, Canada, 8Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel,

9Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden, 10Merck, Whitehouse Station, NJ, United States

29

Aim: C-WORTHy TN

Hezode, C. et al. EASL 2014, Abstract #O10

• To assess the efficacy/safety of an 8- to 12-week regimen of MK-5172 + MK-8742 ± weight-based ribavirin in treatment-naïve, noncirrhotic patients with HCV G1 infection

• Key inclusion/exclusion criteria:– Treatment-naïve patients ≥ 18 years old with chronic HCV G1a or G1b infection– Liver biopsy or noninvasive test (METAVIR F0-F3)– Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males)– HIV and hepatitis B virus negative– Alanine aminotransferase (ALT) as aspartate aminotransferase (AST) <350 IU/L

Treatment-naïve, noncirrhotic 12 weeks ± RBV

(n=65)

Treatment-naïve Noncirrhotic

8-12 weeks ± RBV(n=94)

Treatment-naïveCirrhotic

12-18 weeks ± RBV(n=123)

Null respondersCirrhotic/noncirrhotic

12-18 weeks ± RBV(n=130)

HIV/HCV coinfected Noncirrhotic

12 weeks ± RBV(n=59)

30

Study Design

SVR, sustained virologic response; TW = treatment week.Hezode, C. et al. EASL 2014, Abstract #O110

RBV-Containing Regimen RBV-Free Regimen

MK-5172 (100 mg)MK-8742 (20 mg)+ RBV

MK-5172 (100 mg)MK-8742 (50 mg)+ RBV

MK-5172 (100 mg)MK-8742 (50 mg)+ RBV

MK-5172 (100 mg)MK-8742 (50 mg)

MK-5172 (100 mg)MK-8742 (50 mg)

MK-5172 (100 mg)MK-8742 (50 mg)+ RBV

PART ASVR24

(AASLD 2013)

PART BFollow-up ongoing

SVR4/8

at ≥SVR4(28/30 SVR8)

100% at SVR8

Study Week

Pa

rt A

Pa

rt B

G1a/bN=25

G1a/bn=27

G1bn=13

G1an=30

G1a/bn=33

G1an=31

D1 TW4 TW8 TW12 SVR4 SVR8 SVR12 SVR24

31

C-WORTHy (A+B) – Overall Efficacy (SVR4-24)*Intention-to-Treat (Nonvirologic Discontinuation = Failure)

Treatment Week 4 End of Treatment SVR0

25

50

75

100100 100

83

95 96 94100 100 98

8 weeks with RBV 12 weeks with RBV 12 weeks (no RBV)

HC

V R

NA

BL

OQ

(<

25

IU

/mL

), %

Pa

tie

nts

*Part A: 100% of patients have completed SVR24; Part B: 8-week arm, 93% of patients have completed SVR8; 12-week arms, 100% of patients have completed SVR8; 2 patients (Part A), 2 patients (Part B) discontinued early (and are counted as failures).Hezode, C. et al. EASL 2014, Abstract #O110

4-24

30/30 81/85 44/44 30/30 82/85 44/44 25/30 80/85 43/44

32

Summary

• Efficacy

– MK-5172/MK8742 once daily with or without RBV for 12 weeks is highly efficacious with a SVR of 94%-98%

– MK-5172/MK-8742 + RBV for 8 weeks in patients with HCV G1a infection had an SVR44/8 of 83%

– Most common type of virologic failure was relapse after a treatment duration of 8 weeks

• Safety

– All treatment regimens were generally safe and well-tolerated

– There were no early discontinuations due to drug-related Aes

– No grade 3 or 4 laboratory abnormalities

Hezode, C. et al. EASL 2014, Abstract #O110

33

Abstract #O56

Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in Treatment-

Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study

Kris V. Kowdley1, Stuart C. Gordon 2, K. Rajender Reddy3, Lorenzo Rossaro4, David E. Bernstein5, Di An6, Evguenia S. Svarovskaia6, Robert H. Hyland6, Phillip S. Pang6,

William T. Symonds6, John G. McHutchison6, Andrew J. Muir7, Paul J. Pockros8, David C. Pound9, Michael W. Fried10

1Virginia Mason Medical Center, Seattle, WA, USA; 2Henry Ford Health System, Detroit, MI, USA; 3Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4University of

California Davis Medical Center, Sacramento, CA, USA; 5North Shore University Hospital, Manhasset, NY, USA; 6Gilead Sciences, Inc., Foster City, CA; 7Division of Gastroenterology and Duke Clinical Research

Institute, Duke University School of Medicine, Durham, NC, USA; 8Scripps Clinic, La Jolla, CA; 9Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, USA; 10University of North Carolina at Chapel Hill,

Chapel Hill, NC, USA

34

1. Lawitz E, et al. Lancet. 2014;383:515-23Kowdley, K. et al. EASL 2014, Abstract #O56

Background and AimsGT 1 Treatment-Naïve (ION-3)

• LDV/SOF ± RBV for 8 weeks and LDV/SOF for 12 weeks demonstrated high SVR rates in the Phase 2 LONESTAR study in treatment-naïve HCV patients without cirrhosis1

• To evaluate whether LDV/SOF for 8 weeks is effective for HCV treatment-naïve, non-cirrhotic, GT 1 patients or if RBV or a longer treatment duration of 12 weeks is required to achieve high SVR rate

35

• GT 1 treatment-naïve patients without cirrhosis• Broad inclusion criteria

– No upper age or BMI limit– Opiate substitution therapy allowed

• 647 patients randomized 1:1:1 across three arms• Stratified by HCV subtype (1a or 1b)

LDV/SOF

LDV/SOF

LDV/SOF + RBV

Wk 0 Wk 8 Wk 12 Wk 24Wk 20

SVR12

SVR12

SVR12

Kowdley, K. et al. EASL 2014, Abstract #O56

Study DesignGT 1 Treatment-Naïve (ION-3)

36

Error bars represent 95% confidence intervals.Kowdley, K. et al. EASL 2014, Abstract #O56

Results: Non-Inferiority ComparisonGT 1 Treatment-Naïve (ION-3)

0

20

40

60

80

100

p=0.70 p=0.30

206/216

8 Weeks 12 Weeks

LDV/SOFLDV/SOF LDV/SOF + RBV

201/216202/215 206/216

SV

R12

(%

)p=0.52

37

Kowdley K, et al. NEJM In PressKowdley, K. et al. EASL 2014, Abstract #O56

ConclusionsGT 1 Treatment-Naïve (ION-3)

• LDV/SOF ± RBV for 8 or 12 weeks results in highSVR12 rates

• No difference in efficacy among the groups was observed

• Host and viral factors traditionally associated with lower SVR rates did not affect SVR12 rates

• LDV/SOF ± RBV was safe and well tolerated

– RBV contributed to a higher incidence of AEs and laboratory abnormalities

• An 8 week LDV/SOF treatment regimen is a safe and effective treatment for treatment-naïve non-cirrhotic patients with HCV GT 1 infection

38

Abstract #P1324

Z. Younossi1, M. Stepanova1, P. Marcellin2, N. Afdhal3, F. Nader1, S. Hunt4

1Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States, 2Viral Hepatitis Research Unit, Hopital Beaujon, Clichy, France, 3Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, 4Betty and Guy Beatty Center for Integrated Research, Inova Health System,

Falls Church, VA, United States

Ledipasvir (LDV) and Sofosbuvir (SOF) Combination Improves Patient-Reported Outcomes (PRO) During Treatment of

Chronic Hepatitis C (CH-C) Patients: Results From the ION-1 Clinical Trial

39

Background

Younossi, Z. et al. EASL 2014, Abstract #P1324

• Interferon-based treatment for chronic hepatitis C (CH-C) causes substantial side effects that negatively impact patient-reported outcomes (PROs).

• The use of ribavirin (RBV) is associated with additional burden on PROs

• Emerging interferon- and ribavirin-free regimens are expected to result in less if any adverse events and, therefore, better PROs in patients undergoing anti-HCV treatment

40

Aim


• To assess patient reported outcome of CH-C patients treated with sofosbuvir and ledipasvir(LDV+SOF) with or without ribavirin in the 12 weeks arms of ION-1 clinical trial

41

SOF 400 mg + LDV 90 mg + RBV 1000/1200 mg daily n=217

Week 0

PROs

12

Follow-Up Week 12

Follow-Up Week 12

16 24

SOF 400 mg + LDV 90 mg dailyn=214

4

PROs PROs PROs PROs PROs

82

PROs


ION-1 Multicenter Phase 3 Clinical Trial • 431 HCV genotype 1 treatment-naïve patients in 12 weeks arm of the study• Clinical data: 52±11 years old, 59% male, 16% cirrhotic, 56% from USA• Patient-reported outcome (PRO) questionnaires were completed at

baseline, during and post-treatment: SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP

• Treatment-related anemia: 74.2% in LDV+SOF+RBV, 7.0% in LDV+SOF (p<0.01)

• SVR rate: 97.2% in LDV+SOF+RBV, 98.6% in LDV+SOF (p=NS)• On-treatment and post-treatment HCV RNA viral load results were blinded to patients and investigators

42

0.65

0.7

0.75

0.8

0.85

0.9

0.95

SF-36:physicalHRQL

SF-36:mentalHRQL

FACIT-F:fatigue

FACIT-F:total well-

being

CLDQ-HCV:total HRQL

Workprodictivity

Activityother than

work

No

rma

lize

d P

RO

SOF+LDV+RBV

SOF+LDV

p=NS p=NS p=0.0006 p=0.053 p=NS p<0.0001

p=0.0017

P-values represent differences between treatment regimensNS – not significant (p>0.05)


PRO Scores in Patients Treated With Ledipasvir and Sofosbuvir With or Without Ribavirin: Treatment Week 12

SF-36:physicalHRQL

SF-36:mentalHRQL

FACIT-Ffatigue

FACIT-Ftotal

well-being

Workproductivity

CLDQ-HCV;

total HRQL

Activityother than

work

p=NS p=0.0006 p=0.053 p=<0.0001p=NS

p=<0.0017

0.95

0.9

0.85

0.8

0.75

0.7

0.65

No

rma

lize

d P

RO

SOF+LDV+RBV

SOF+LDV

p=NS

43

P-values represent differences between treatment regimens* - p<0.05 for the difference from baseline

-0.09

-0.04

0.01

0.06

SF-36:physicalHRQL

SF-36:mentalHRQL

FACIT-F:fatigue

FACIT-F:total well-

being

CLDQ-HCV:total HRQL

Workprodictivity

Activityother than

work

No

rma

lize

d P

RO

ch

an

ge

fro

m b

as

elin

e

SOF+LDV+RBV SOF+LDV

p=0.0009

p=0.0050

p<0.0001

p=0.0001

p=0.0016

p=0.0001

p=0.0010

* * * * * *

* * *


Changes in PRO Scores From Baseline to Treatment Week 12

0.06

0.01

-0.04

-0.09

SOF+LDV+RBV SOF+LDV

No

rma

lize

d P

RO

Ch

an

ge

Fro

m B

as

eli

ne

SF-36:physicalHRQL

SF-36:mentalHRQL

FACIT-Ffatigue

FACIT-Ftotal

well-being

Workproductivity

CLDQ-HCV;

total HRQL

Activityother than

work

p=0.0009

p<0.0001

p=0.0001

p=0.0001

p=0.0010

p=0.0016

p=0.0050

44

Conclusions


• Treatment-naïve genotype 1 CH-C patients receiving sofosbuvir+ledipasvir have similar SVR and superior PROs compared to patients receiving the same regimen with added ribavirin

• The RBV-free regimen is associated with improved PRO scores during treatment and after achieving SVR-12

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• During this year’s EASL meeting (ILC-2014, London, England), exciting data regarding a number of new regimens to treat HCV were presented

• The data presented showed that these regimens have high efficacy, improved safety, and shorter duration of treatment

• Furthermore, some of these regimens can clearly improve patient reported outcomes such as fatigue and HRQL

1 Zobair Younossi, MD, MPH, FACG Falls Church, VA, United States This activity is supported by an...

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Transcript of 1 Zobair Younossi, MD, MPH, FACG Falls Church, VA, United States This activity is supported by an...